Hematopoietic stem cell transplantation is an effective treatment for a broad range of hematologic, immune, metabolic and malignant diseases. This Is a high-risk procedure which may be complicated by graft-vs.-host disease, graft rejection, regimen related toxicities and infectious complications. Improved therapeutic strategies are needed to improve the outcome and reduce the toxicities. Graft-vs.-host disease is the major complication limiting the broader application of hematopoietic transplantation and novel, more effective therapy is needed. Specific Aim: We propose a Phase II Randomized, Multicenter Trial Comparing Standard GVIHD Prophylaxis with Etanercept vs. Pentostatin/ATG in Unrelated Donor HCT. This is a multicenter prospective study to examine two promising approaches for prevention of GVHD, with the pentostatin arm derived from a large phase l/ll study at our center(Parmar, et al 2010) and the etanercept arm developed with collaborators at the University of Michigan. The proposed study will test the hypothesis that the addition of etanercept or pentostatin/ATG to standard GVHD prophylaxis will improve 6-month NRM rates for patients undergoing matched unrelated HCT for the treatment of hematologic malignancies when compared to historical rates from the CIBMTR database with standard of care GVHD prophylaxis. The primary endpoint for this trial will be NRM at 6 months post-transplant. Secondary endpoints are two-year survival from the time of transplant, incidences of neutrophil and platelet engraftment, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, current immunosuppressive free survival, relapse, infections, and adverse events. Biologic correlates will be assessed to predict development of GVHD and its prognosis. The goal is to identify the most promising regimen for further definitive testing in a future Phase III study. The application is a competitive renewal of the University of Texas- MD Anderson Cancer Center (MDACC) as a Core Clinical Center for Blood and Marrow Transplant-Clinical Trials Network. MDACC is the nation's largest NCI designated Comprehensive Cancer Center, and a leader in clinical and translational research in hematopoietic transplantation. We are committed to the success of the BMT-CTN and continue to be leaders in the organization. We are a major contributor to the development of BMT-CTN studies and active accrue patients to its studies.